Stratified and cryogenically stored vaccines, process for their preparation

Abstract

A composition comprising at least one antigenic medium and at least one adjuvant, wherein the at least one antigenic medium and the at least one adjuvant each comprise one or more phases which are distinct from each other when the composition is in a solid state, and the composition is in the liquid state when its temperature is greater than or equal to 4° C.

1. A composition comprising:
 at least one frozen antigenic medium; and 
 at least one frozen adjuvant; 
 wherein the composition is in a solid state, and 
 wherein the at least one frozen antigenic medium and the at least one frozen adjuvant each comprise one or more phases which are distinct from each other; and 
 wherein the composition would be in the liquid state at a temperature greater than or equal to 4° C. 
 
     
     
       2. The composition as defined in  claim 1 , wherein the various phases comprising the composition in the solid state are adjacent to at most two distinct phases. 
     
     
       3. The composition as defined in  claim 2 , wherein the various phases comprising the composition in the solid state are arranged in a stratified manner in said composition. 
     
     
       4. The composition as defined in  claim 3 , wherein the various phases comprising the composition in a solid state are superposed one on top of another. 
     
     
       5. The composition as defined in  claim 1 , wherein the antigenic medium comprises a lyophilisate of antigenic material. 
     
     
       6. The composition as defined in  claim 1 , wherein the antigenic medium is an aqueous or aqueous-alcoholic phase of antigenic material. 
     
     
       7. The composition as defined in  claim 1 , comprising at least one aqueous or aqueous-alcoholic adjuvant phase comprising at least one water-soluble salt of a metal cation and an organic acid,
 wherein said organic acid possesses at least one phosphoric group or one carboxyl group. 
 
     
     
       8. The composition as defined in  claim 7 , in which the at least one water-soluble salt of a metal cation is a salt of manganese, aluminum, calcium or zinc. 
     
     
       9. The composition as defined in  claim 7 , in which the at least one water-soluble salt comprises a salt of glycerophosphoric, acetic, lactic, tartaric, malic, citric, pyruvic, gluconic, glucuronic, fructoheptonic, gluconoheptonic, glucoheptonic, glutamic, or aspartic acids; or of methionine. 
     
     
       10. The composition as defined in  claim 9 , in which the at least one water-soluble salt comprises manganese gluconate, calcium gluconate, zinc gluconate, calcium fructoheptonate, calcium glycerophosphate, soluble aluminum acetate or aluminum salicylate. 
     
     
       11. The composition as defined in  claim 1 , comprising at least one aqueous or aqueous-alcoholic adjuvant phase comprising a surfactant or a mixture of surfactants, having an overall HLB number of between 5 and 15. 
     
     
       12. The composition as defined in  claim 11 , in which the surfactant or the mixture of surfactants is a modified fatty substance having an overall HLB number of between 6 and 14. 
     
     
       13. The composition as defined in  claim 12 , in which the modified fatty substance is an ethoxylated derivatives of an oil having a number of EOs of between 1 and 60. 
     
     
       14. The composition as defined in  claim 13 , comprising alkoxylated derivatives of maize oil, mixtures of alkoxylated derivatives of maize oil, having an overall HLB number of between 10 and 14, or ethoxylated derivatives of castor oil or mixtures of alkoxylated derivatives of castor oil, having an overall HLB number of between 7 and 10. 
     
     
       15. The composition as defined in  claim 1 , comprising at least one aqueous or aqueous-alcoholic adjuvant phase comprising an alkoxylated derivative of an ester of a fatty acid and of a polyol or an alkoxylated derivative of an ether of a fatty alcohol and of a polyol. 
     
     
       16. The composition as defined in  claim 15 , in which the alkoxylated derivative of the ester of the fatty acid and of the polyol is a triglyceride of an alkoxylated fatty acid, the alkoxylated ester of polyglycerol and of a fatty acid, the alkoxylated ester of the fatty acid with a hexol or the alkoxylated ester of the fatty acid with a hexol anhydride. 
     
     
       17. The composition as defined in  claim 16 , wherein the hexol is sorbitol or mannitol. 
     
     
       18. The composition as defined in  claim 16 , wherein the hexol anhydride is sorbitan or mannitan. 
     
     
       19. The composition as defined in  claim 15 , wherein the esters of fatty acids comprise acyl radicals containing from 12 to 22 carbon atoms. 
     
     
       20. The composition as defined in  claim 19 , wherein said acyl radicals contain from 16 to 18 carbon atoms. 
     
     
       21. The composition as defined in  claim 19 , in which the acyl radicals of said fatty acid esters are derived from oleic, ricinoleic or isostearic acids. 
     
     
       22. The composition as defined in  claim 15 , comprising at least one aqueous or aqueous-alcoholic adjuvant phase comprising an ethoxylated derivative of mannitan oleate having a number of EOs of between 5 and 15. 
     
     
       23. The composition as defined in  claim 22 , comprising an ethoxylated derivative of mannitan oleate having a number of EOs of between 7 and 11. 
     
     
       24. The composition as defined in  claim 1 , comprising at least one aqueous or aqueous-alcoholic adjuvant phase comprising:
 a) one or more compounds of formula (I):
   R 1 —O-(G) x -H  (I) 
 
 
       in which R 1  represents a saturated or unsaturated, linear or branched hydrocarbon radical containing from 1 to 30 carbon atoms, G represents the residue of a saccharide and x represents a decimal number of between 1 and 5, and optionally
 b) one or more compounds of formula (II):
   R 2 —OH  (II) 
 
 
       in which R 2  represents, independently of R 1 , a saturated or unsaturated, linear or branched hydrocarbon radical containing from 8 to 30 carbon atoms. 
     
     
       25. The composition as defined in  claim 24 , for which, in the formula (I), the number x, is between 1 and 3. 
     
     
       26. The composition as defined in  claim 25 , wherein the average degree of polymerization of the saccharide is between 1.05 and 2.5. 
     
     
       27. The composition as defined in  claim 26 , wherein the average degree of polymerization of the saccharide is between 1.1 and 2.0. 
     
     
       28. The composition as defined in  claim 27 , wherein the average degree of polymerization of the saccharide is less than or equal to 1.5. 
     
     
       29. The composition as defined in  claim 24 , for which, in the formula (I), G represents more particularly a glucose residue or a xylose residue. 
     
     
       30. The composition as defined in  claim 24 , for which, in the formula (I), the radical R 1  represents a radical containing from 5 to 22 carbon atoms chosen from pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, uneicosyl, docosyl, heptadecenyl, eicosenyl, uneicosenyl, docosenyl, heptadecadienyl or decenyl radicals, said radicals being linear or branched. 
     
     
       31. The composition as defined in  claim 30 , for which, in the formula (I), R 1  represents a radical containing from 8 to 20 carbon atoms, said radicals being linear or branched. 
     
     
       32. The composition as defined in  claim 24 , for which, in the formula (II), R 2  represents a radical containing from 8 to 22 carbon atoms chosen from octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, uneicosyl, docosyl, heptadecenyl, eicosenyl, uneicosenyl, docosenyl, heptadecadienyl or decenyl radicals, said radicals being linear or branched. 
     
     
       33. The composition as defined in  claim 24 , for which, when the adjuvant phase comprises at least one compound of formula (I) and at least one compound of formula (II), the compound of formula (I)/compound of formula (II) weight ratio is between 10/90 and 90/10. 
     
     
       34. The composition as defined in  claim 33 , wherein the weight ration is between 10/90 and 60/40. 
     
     
       35. The composition as defined in  claim 1 , comprising at least one oily adjuvant phase, wherein when the antigenic medium comprises a lyophilisate comprising one or more antigens, the composition also comprises either:
 at least one aqueous or aqueous-alcoholic adjuvant phase comprising one or more water-soluble salts of metal cations and organic acids,
 wherein said organic acids possess at least one phosphoric group or one carboxyl group; or 
 
 a diluent phase for the antigenic medium. 
 
     
     
       36. The composition as defined in  claim 35 , wherein the at least one oily adjuvant phase is a mineral oil, a synthetic oil, a vegetable oil or an animal oil. 
     
     
       37. The composition as defined in  claim 36 , comprising in combination (i) the oil or the mixture of oils comprising the oily phase and (ii) a nonionic surfactant or a mixture of nonionic surfactants. 
     
     
       38. The composition as defined in  claim 37 , wherein said nonionic surfactant comprises oleic, ricinoleic or ketostearic acid; or a derivative thereof. 
     
     
       39. The composition as defined in  claim 38 , wherein said nonionic surfactant comprises a mannitol oleate or a derivative of mannitol oleate obtained by grafting a hydrophilic functional group. 
     
     
       40. The composition as defined in  claim 39 , wherein said hydrophilic functional group comprises an amide, amine, alcohol, polyol or carboxyl functional group; an ethoxy, propoxy and/or butoxy radical; a mannitan oleate; or a derivative thereof. 
     
     
       41. The composition as defined in  claim 35 , comprising a single oily adjuvant phase. 
     
     
       42. The composition as defined in  claim 41 , wherein, in the solid state, the oily phase comprises the bottom phase of said composition. 
     
     
       43. The composition as defined in  claim 1 , further comprising at least one diluent phase for at least one of the antigenic phases, whose diluent character is expressed when said composition is in the liquid state and which, when the composition is in the solid state, is distinct from the antigenic phase or from the antigenic phases and from the adjuvant phase or from the adjuvant phases. 
     
     
       44. The composition as defined in  claim 1 , further comprising at least one diluent phase for at least one of the adjuvant phases, whose diluent character is expressed when said composition is in the liquid state and which, when the composition is in the solid state, is distinct from the antigenic phase or from the antigenic phases and from the adjuvant phase or from the adjuvant phases. 
     
     
       45. The composition as defined in  claim 1 , which does not comprise an oily phase. 
     
     
       46. The composition as defined in  claim 35 , comprising an antigenic phase and an oily adjuvant phase. 
     
     
       47. The composition as defined in  claim 35 , comprising an antigenic phase, an oily adjuvant phase and a diluent phase for the antigenic phase. 
     
     
       48. The composition as defined in  claim 46 , wherein, in the solid state, the oily phase comprises a bottom layer and the antigenic phase a top phase. 
     
     
       49. An immunogenic composition comprising the composition as defined in  claim 1  and a frozen carrier suitable for parenteral or intravenous injection. 
     
     
       50. A composition prepared by the process comprising:
 freezing at least one antigenic medium into a solid state, 
 adding at least one adjuvant in a liquid state to the antigenic medium, and 
 freezing the at least one adjuvant into a solid state, 
 
       wherein the at least one antigenic medium and the at least one adjuvant each comprise one or more phases which are distinct from each other when the composition is in a solid state, and wherein the composition would exist in a liquid state when its temperature is greater than or equal to about 4° C.